Breast disorders are so common that B. Smith & W. Souba, Breast disease, p. 1, in Breast Disease 2, D. Wilmore, et al. (eds) (New York, Scientific America) (1995) estimate that one of every two women will consult her physician about a breast disorder at some point in her life. Clinically, the most useful classification system for benign breast disease is based on symptoms and physical findings. The six general categories of symptoms are:    1. Physiologic swelling and tenderness;    2. Nodularity, significant lumpiness, both cyclic and non-cyclic;    3. Mastalgia, severe pain, both cyclic and non-cyclic;    4. Dominant lumps, including gross lumps and fibroadenomas;    5. Nipple discharge, including intraductal papilloma and duct ectasia; and    6. Infections and inflammation, including subareolar, abscesses, lactational mastitis, breast abscesses and Mondor's Disease. See J. Isaacs, Benign Neoplasms, in D. Marchant, Breast Disease, p. 65-68 (WB Saunders, Philadelphia, Pa.) (1997).
Swelling, breast pain, and nodularity (Categories 1 and 2) are often grouped together and referred to as fibrocystic disease or changes. However, aggregating these categories may be problematic as the various causes of these symptoms may be isolated to determine the specific cause of the condition and the resultant treatment option to be undertaken. For example, women on oral contraceptives or hormone replacement therapy may experience swelling and breast tenderness (Category 1). By reducing or eliminating the estrogen replacement therapy, the breast pain or swelling may be reduced. Alternatively, breast pain may be caused by trauma, chest wall pain, or by costochondritis.
Dominant lumps (Category 4) are generally clinically benign breast lesions that are distinct, persistent, and relatively unchanging. The lesions that are represented by these lumps include macrocysts, galactoceles, and fibroadenomas. These lumps generally do not respond to hormonal therapy that may be effective in treating nodularity or breast pain.
Fibroadenomas (Category 4) represent the most common benign solid tumor of the female breast. They are typically seen in women in the third decade of life although they are sometimes seen in postmenopausal women. Fibroadenomas may respond to hormonal therapy and may change in size throughout the menstrual cycle.
Treatment options for breast disorders fall into two major categories, pharmacologic therapy and surgical approaches. Before initiating any treatment, an assessment of dietary, hormone therapy and other factors must be taken into consideration. Women who use estrogen replacement therapy or oral contraceptives may discontinue therapy. In addition, dietary modification such as a reduction in saturated fat intake and caffeine consumption may reduce breast pain in certain women.
Drug treatment for breast pain is tailored to the severity of pain, chances of improvement with each drug, and potential adverse effects. P. Holland & C. Gately, Drugs, 48(5):709-716 (1994). Women with mild pain may be administered 6-8 capsules of gamma-linolenic acid (also known as “gamolenic acid” or “GLA”) (40 mg) per day. The side effects associated with GLA are mild. For severe pain, the only approved treatment option is danazol, which is typically given in a dose of 100 mg to 200 mg per day. Danazol is highly effective, although it causes androgenic side effects which may reduce patient compliance. Controlled trials demonstrate that at oral doses of 200 mg to 400 mg per day, danazol produces a favorable clinical response in 70% to 80% of patients. C. Hinton, et al., British J. Clinical Practice, 40(8):326-30 (1986); R. Mansel, et al., Lancet, 8278: 928-933 (1982); and B. Steinbrum, et al., Postgraduate Medicine, 102(5):183-84, 187-87, and 193-94 (1997). In most instances, breast pain and tenderness are significantly relieved by the first month and eliminated in two to three months. Usually elimination of nodularity requires four to six months of therapy. However, high doses of danazol result in adverse side effects, which may include weight gain, voice change, development of facial and chest hair, loss of libido, acne, and central nervous system (“CNS”) symptoms such as depression, anxiety, fatigue, nausea and diarrhea, as well as the inhibition of pregnancy while undergoing treatment. See e.g. Spooner, Classification of Side Effects to Danazol Therapy, Winthrop Laboratories, Surrey, England.
Bromocriptine, tamoxifen, and luteinizing hormone-releasing hormone (LHRH) analogues are not approved for the initial treatment of breast pain and fibrocystic breast disease, but are used to treat breast pain and fibrocystic disease that are resistant to other forms of treatment. The side effects associated with these drugs are severe.
Bromocriptine, which inhibits release of prolactin, is effective in up to 65% of women treated for cyclical mastalgia, i.e. breast pain which occurs in a regular pattern over time, at doses of 5 mg per day. These results were confirmed in a multicenter, randomized, controlled study. K. Nazli et al., Br J Clin Pract., 43: 322-27 (1989); R. Mansel & L. Dogliotti, Lancet, 335 (868):190-193 (1990). Improvement in symptoms was accompanied by a decrease in serum prolactin level. Mild side effects, including nausea, dizziness, headaches, and irritability have been reported in 30% of women, and 10% have complained of more severe side effects. These side effects can be minimized by altering the dosing regimen or reducing the amount of drug administered. However, R. Mansel et al., BR J Surgery, 65(10):724-27 (1978) noted that bromocriptine did not induce a response in patients with non-cyclical breast pain.
In severe cases of breast pain and fibrocystic breast disease, tamoxifen has been prescribed. Controlled trials demonstrated 80% to 90% success in treatment of cyclical mastalgia. I. Fentimen, et al., Br. J. Clinical Prac. Sympt., 68:34-36 (1989). In addition, no difference in response was noted in women who received daily doses of 10 mg per day versus those who received daily doses of 20 mg per day. A decrease in side effects was noted however, in women who received 10 mg per day. I. Fentimen, et al., BR J Surg., 75(9): 845-46 (1988).
Non-steroidal anti-inflammatory drugs (NSAIDs) are sometimes prescribed for the treatment of breast pain. A prospective study of the effectiveness of the topical application of NSAIDs as a gel formulation was carried out in 26 women with severe breast pain. A topical NSAID gel was applied as required and provided rapid relief of pain with no side effects in 81% of the women. A. Irving & S. Morrison, JR Coll Edinb, 43(3):158-9 (1998).
In non-cyclical mastalgia, and especially for chest wall pain, injections of lidocaine 1% (1 ml) and methylprednisone (40 mg) have been shown to be effective. Response rates of 90% have been reported, but about 50% of patients required a second injection 2 to 3 months later. A. Millet & F. Dirbas, Obstetrical and Gynecological Survey, 57(7): 459 (2002).
Miltefosine (also known as MILTEX® and hexadecylphosphocholine) has been used topically to treat cutaneous manifestations of metastatic breast cancer. See e.g. C. Unger et al., Cancer Treat Rev 17: 243-246 (1990); J. Terwogt et al., Br J Cancer, 79: 1158-1161 (1999); and R. Leonard et al., J Clin Oncol, 19: 4150-4159 (2001). These reports indicate that the cytostatic drug, miltefosine, is useful to treat topical lesions arising from a primary neoplasia event in the breast. However, the drug does not treat neoplastic lesions within the breast tissue and the cutaneous metastatic tissue need not be localized to breast skin. Therefore, the drug is merely acting topically at the site of administration. Further, the drug is not effective at treating the underlying disease of the breast.
Treatment of disorders and diseases of the breast and underlying musculature by traditional methods of oral or systemic administration is associated with a significant number of side effects and other complications that limit their use. For example, the normal digestive process may reduce bioavailability of drugs, requiring a higher dose be administered in order to achieve the desired effect. In addition, passage of the drag from the liver into the systemic circulation may convert the drug into a metabolite of the drug and cause a variety of untoward side effects. Either of these problems may cause patients to avoid their medications and disregard their doctors' treatment regimes.
It is therefore an object of the present invention to provide formulations and methods of administration to increase patient compliance and comfort during the treatment of diseases and disorders of the breast and chest.
It is a further object of the present invention increase the bioavailability of drug administered topically to the breast or chest as compared to drugs administered systemically.